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| Status |
Public on Mar 06, 2023 |
| Title |
TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy. |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
• Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA-seq, ATAC-seq, protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEAD1 by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R- LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA-mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from DCM patients with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.
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| Overall design |
Integrative analysis of single cell RNA-seq and ATAC-seq in knock-in mice with Lmna Q353R mutation
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| Contributor(s) |
Ko T, Ito M, Sassa T, Nomura S, Toyooka K, Umezawa A, Nitta R, Aburatani H, Komuro I |
| Citation(s) |
37058558 |
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| Submission date |
Dec 15, 2021 |
| Last update date |
May 03, 2023 |
| Contact name |
Shintaro Yamada |
| E-mail(s) |
shintayamada-tky@g.ecc.u-tokyo.ac.jp
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| Phone |
81338155411
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| Organization name |
The University of Tokyo
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| Department |
Department of Cardiovascular Medicine
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| Street address |
7-3-1, Hongo, Bunkyo-ku
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| City |
Tokyo |
| ZIP/Postal code |
113-8655 |
| Country |
Japan |
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| Platforms (3) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA789236 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE190977_RAW.tar |
940.8 Mb |
(http)(custom) |
TAR (of BW, H5, MTX, TSV) |
| GSE190977_TT10_treatment_RPKM_batch_corrected_matrix.csv.gz |
1.2 Mb |
(ftp)(http) |
CSV |
| GSE190977_iPSCM_bulk_RNAseq.csv.gz |
687.0 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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